This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Peripherally induced Regulatory T cell (iTregs) is the predominant source of T cell suppressor activity in the human immune system. As such, the possibility to control their development holds a tremendous therapeutic promise. Our lab has established a cell culture system that recapitulates the generation of functional iTregs ex vivo from primary human T cells. With this system and using a broad range of cellular, molecular, biochemical and imaging approaches, we will elucidate phenotypic and functional properties of these newly generated suppressor T cells and will shed light upon the phenomenon of their occurrence. The ultimate goal is to control the shift of the T cell response from effector to tolerogenic or vice-versa. The Specific Aims of this proposal are: + Aim 1) Test the hypothesis that a distinctive population of functional human Treg cells can be generated in vitro from conventional CD4+CD25- T cells. + Aim 2) Test the hypothesis that the induction of suppressor activity requires the molecular cross-talk and integration of different signaling pathways. The results ought to provide a solid foundation to support the development of rational strategies to induce, direct or restore the normal immunological activity in different pathologies, such as autoimmunity, chronic inflammation or cancer. This project has clear and direct relevance to human health: the capacity to modulate the development and/or response of Tregs may become instrumental in controlling the dynamic plasticity of the immune response.